Cyclothiazide acts at a site on the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor complex that does not recognize competitive or noncompetitive AMPA receptor antagonists
Desai, M.A.; Burnett, J.P.; Ornstein, P.L.; Schoepp, D.D.
Journal of Pharmacology and Experimental Therapeutics 272(1): 38-43
1995
ISSN/ISBN: 0022-3565 PMID: 7529311 Document Number: 452573
Activation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtype of ionotropic glutamate receptors by certain agonists, including AMPA and glutamate, has been shown to result in a rapid desensitization of the receptor. This desensitization is profoundly inhibited by the benzothiadiazide diuretic, cyclothiazide. We previously reported that cyclothiazide potentiates AMPA-induced (3H)norepinephrine ((3H)NE) release from rat hippocampal slices. We used this system to investigate the possible interaction of cyclothiazide with various AMPA receptor antagonists, including the competitive antagonist LY293558 and the 2,3-benzodiazepine noncompetitive antagonist GYKI 53655. Cyclothiazide significantly potentiated both AMPA- and KA-induced (3H)NE release from slices of the rat hippocampus. LY293558 and GYKI 53655 inhibited the potentiated and nonpotentiated AMPA- and KA-induced (3H)NE release in a concentration-dependent manner. The IC-50 values for inhibition of AMPA- or KA-induced (3H)NE release by either antagonist were not affected by the presence of cyclothiazide. Thus, cyclothiazide seems to interact at a site on the AMPA receptor complex which differs from either the glutamate recognition site or the 2,3-benzodiazepine allosteric site.